Monday, April 18, 2016

A new analysis of 204 studies involving more than 1.4 million people suggests that metformin, the most frequently prescribed stand-alone drug for type 2 diabetes, reduces the relative risk of a patient dying from heart disease by about 30 to 40 percent compared to its closest competitor drug, sulfonylurea.

The study, designed to assess the comparative -- not absolute or individual -- benefits and risks of more than a dozen FDA-approved drugs for lowering blood sugar in type 2 diabetes, is described in the April 19, 2016 issue of the Annals of Internal Medicine. Diabetes now affects almost 10 percent of the U.S. population and poses a growing public health threat, and most people will eventually need drug treatment, the researchers say.

"Metformin looks like a clear winner," says Nisa Maruthur, M.D., M.H.S., assistant professor of medicine at the Johns Hopkins University School of Medicine. "This is likely the biggest bit of evidence to guide treatment of type 2 diabetes for the next two to three years."

Maruthur, the lead author on the meta-analysis, notes that cardiovascular fatalities -- heart attacks and strokes -- are major risks for people with uncontrolled blood sugar, but it has never been clear if one diabetes drug is better than another at lowering these fatalities. Other diabetes-related complications include blindness, kidney failure and limb amputations.

This review, Maruthur says, provides a much-needed update to two previous analyses, the last one published in 2011. Since then, researchers have published more than 100 new studies comparing the effectiveness of various blood sugar-lowering drugs, and several new drugs have also come on the market since the last report.

Of the total 204 studies analyzed, 50 spanned several continents, while others were conducted across Europe, Asia and the United States. Most of the studies were short term, with only 22 mostly observational studies lasting more than two years. Participants in the studies were generally overweight with uncontrolled blood sugar levels. Many studies excluded the elderly and those with significant health problems. Just shy of half of the studies made no mention of race or ethnicity. When researchers did report that information, only 10 to 30 percent of participants were nonwhite.

Maruthur says the new analysis not only looked at cardiovascular disease but also other drug effects, including glucose control, and common side effects, such as weight gain, hypoglycemia and gastrointestinal problems. Because the majority of patients with type 2 diabetes end up using multiple blood sugar-lowering drugs, Maruthur and her team also evaluated how the drugs performed when used alone or in combination. While some of the various studies' participants were on insulin, this injectable drug was only evaluated when used in combination with other drugs.

Among other findings, the new review revealed that DPP-4 inhibitors, a class of anti-diabetic drugs that were very new at the time of the 2011 review, were clearly less effective at lowering blood sugar levels compared to metformin and sulfonylureas.

In terms of side effects, a new class of drugs known as SGLT-2 inhibitors, which work by shuttling excess glucose out of the body through urine, caused yeast infections in 10 percent of users, a side effect unique to this drug, Maruthur says. However, SGLT-2 inhibitors, along with another drug class known as GLP-1 receptor agonists, helped patients lose weight. Sulfonylureas, on the other hand, caused weight gain and resulted in the highest rates of hypoglycemia, or too-low blood sugar, among the oral medications.

Cautioning that such meta-analyses can be limited because of differences in research protocols and measurements across studies, Maruthur and her colleagues took steps to ensure that only studies using similar methods were combined. Also, they excluded from their analysis any studies that included patients taking additional, nonstudy diabetes drugs.

Overall, Maruthur says, the results indicate that metformin, which has been around since the late 1990s, works just as well, if not better, than sulfonylureas, which have been on the market since the late 1950s/1960s, and diabetes drugs that have appeared on the market more recently. She says the new findings are in line with the current recommendation that metformin be used as a first-line therapy. The real question arises, Maruthur says, when patients and doctors must choose a second drug to be used in combination with the metformin.

"The medications all have different benefits and side effects, so the choice of second-line medications must be based on an individual patient's preferences," Maruthur says.

Maruthur and her team's work will be published alongside the report they wrote for the Agency for Healthcare Research and Quality, the funding agency for the study, detailing the hundreds of studies included in Maruthur's analysis and an exhaustive summary. Both the American College of Physicians and the Veterans Association plan to use these publications to update their guidelines.

The cost of diabetes drugs is a major consideration when prescribing. While metformin is available as a relatively cheap generic, many newer drugs carry a hefty price tag. In 2014, per-person spending was higher for diabetes drugs for any other class of traditional drugs, in part because over half the prescriptions filled for diabetes were for nongenerics.

Friday, April 15, 2016

A type 2 diabetes treatment has been found to also have 'off-label' benefits for glucose control in the liver and in fatty cells known as adipose.1 Presented at The International Liver CongressTM 2016 in Barcelona, Spain, today, the study shows that exenatide, a treatment that targets the pancreas to improve glucose absorption, enhances glucose uptake and reduces insulin resistance in the liver and in adipose tissue.

Non-alcoholic fatty liver disease (NAFLD) is a condition in which fat builds up in the liver. In some cases this accumulation of fat can cause inflammation of the liver and eventually lead to permanent scarring (cirrhosis), which can seriously impair the liver's ability to function. NAFLD is closely associated with obesity and diabetes and the consequences of the condition can be grave, representing a major global public health problem.2 Two large European studies reported NAFLD prevalence rates of between approximately 43% and 70% in adults with type 2 diabetes.3

"There has been much discussion around the benefit of using injectable diabetes treatments, such as exenatide, on other tissues than the pancreas to improve glucose control," said Dr Amailia Gastaldelli, Institute of Clinical Physiology, CNR, Pisa, Italy, University of Texas Health Science Center, San Antonio, USA, and lead author of the study. "This is why we set out to evaluate the effects of exenatide on the liver and adipose tissue; to better understand the benefits this treatment could offer to a wider group of patients."

Male participants (n=15) with a fatty liver index score of >30 (a classification system that ranges from 0 to 100)4 were tested on two occasions. Those with a score <30 are deemed to have a negative likelihood of having fatty liver. Exenatide or placebo was injected 30 minutes before an oral glucose test in the double blinded study. The test measured glucose uptake in liver tissue and abdominal adipose tissue glucose uptake.

The results showed that acute exenatide administration (5mcg) decreased glucose production and insulin resistance (p=0.02) in the liver tissue when blood sugars were low. The treatment also improved liver tissue uptake of glucose when it is eaten (p=0.039). Furthermore, exenatide decreased insulin resistance in fatty adipose tissue (p=0.009).

"This interesting study shows promising findings for the many people around the world who suffer from non-alcoholic fatty liver disease," says Professor Tom Hemming Karlsen, EASL Vice-Secretary. "The authors have succeeded in identifying an existing treatment that can improve liver metabolism, which is an important step forward for the hepatology community."

Thursday, April 7, 2016

While controlling blood pressure, blood sugar
and LDL-cholesterol levels reduces the risk of cardiovascular disease in
people with diabetes, only 7 percent of diabetic participants in three
major heart studies had recommended levels of these three factors,
according to research from the Heart Disease Prevention Program at the
University of California, Irvine School of Medicine.

The findings
illustrate the need for persons with diabetes to better manage their
blood pressure, blood sugar and LDL-cholesterol levels, which are prime
indicators of future cardiovascular disease. The diabetic participants
surveyed in the UCI review were enrolled in the three heart studies
between the late '80s and early 2000s, when treatment was not as good as
it is now. Still, more recent data show that only 25 percent of
Americans with diabetes achieve all three of these targets.

The
good news is that those in the heart studies who did control all three
factors had a 62 percent lower risk of developing cardiovascular
disease, according to Nathan D. Wong, lead author of the UCI report,
which appears online in Diabetes Care.

"But we have done a dismal
job nationally at getting most of our patients with diabetes controlled
for even just these three measures," said Wong, director of the Heart
Disease Prevention Program and a cardiology professor at UCI.

"Since
cardiovascular diseases - including coronary heart disease, stroke and
heart failure - are leading causes of death for people with diabetes,
these findings underscore the value of achieving target or lower levels
of these modifiable risk factors," he added.

The researchers compared measurements of
the three key factors to American Diabetes Association guidelines that
were in effect at the time - blood pressure under 130/80 mmHg, LDL (or
bad) cholesterol less than 100 mg/dL and blood HbA1c (glycated
hemoglobin) under 7 percent. Forty-one percent of the study group were
on target in one of the three categories; 27 percent had achieved two of
the benchmarks; but only 7 percent met the recommended scores in all
three.

Study participants' control of individual and composite
factors was also examined in relation to the occurrence of new
cardiovascular events (including heart attacks, coronary deaths,
strokes, heart failure, percutaneous interventions and bypass surgeries)
over an average follow-up of 11 years.

Wong said that proper
management of any one factor translated to a 36 percent lower risk,
proper management of any two factors was linked to a 52 percent lower
risk, and proper management of all three factors correlated to a 62
percent lower risk of cardiovascular events compared to those without
any factors controlled.

Blood pressure management appeared to
benefit African Americans and women more than other ethnic groups or
men; however, the converse was true for LDL control.

"Our
analysis of three large U.S. cohorts including persons in whom diabetes
has been diagnosed shows those who were at target levels for HbA1c,
blood pressure and LDL to have substantially lower risks for
cardiovascular disease than persons with diabetes who were not at target
levels for such factors," Wong said. "These findings emphasize the
importance of composite control of these modifiable risk factors to
better address the cardiovascular disease risks seen in persons with
diabetes, the need for the development of healthcare strategies to
better ensure such management, and the need for studies to evaluate and
eliminate barriers to risk factor control in persons with diabetes."